Metal anthracycline complexes as a new class of anthracycline derivatives

Abstract

The anthracycline antibiotics adriamycin and daunorubicin are highly efficient antineoplastic agents; unfortunately their clinic use is limited by the development of a dose-limiting and potentially fatal cardiac toxicity. Although the mechanism of anthracycline cardiac toxicity remains not completely understood, recent studies have suggested that it may be related to the formation of semiquinone free-radical intermediates in vivo and it has been demonstrated that a component of mitochondrial NADH dehydrogenase actively reduces adriamycin. Thus, the hope of finding a non- cardiotoxic but yet active anthracycline antibiotic has prompted the development of a large number of semisynthetic analogs. We have thus proposed the complexation of anthracycline with metal ions as a possible route to new derivatives. We have synthesized complexes of adriamycin, daunorubicin and carminomycin with Fe(II) and Pd(II). The stability constants of these complexes are very high and no release of metal ion is observed when they are injected in the plasma. All these complexes (i) display antitumor activity against P-388 that compares with that of the free drug, (ii) unlike the free drug, they do not catalyze the flow of electrons from NADH to oxygen through NADH dehydrogenase, (iii) they do not exhibit cardiotoxicity when they are tested on cardiac cells in culture.